A chemokine receptor type 3 (which is hereinafter referred to as CCR3) as a member of a chemokine receptor family is a seven-pass transmembrane G protein-coupled receptor which is expressed in a part of eosinophils, basophils, or helper T cells (Non-Patent Document 1).
Eotaxin, which is a CCR3 ligand, is one type of chemokine, named as a chemotactic cytokine, which binds specifically to a CCR3, thus leading to an increased intracellular calcium concentration and a induction of cell shape change, which consequently, results in an increased cell motility function (Non-Patent Document 2). Further, it is suggested that when a CCR3 is activated in eosinophils, the expression of adhesion molecules onto the surface of the eosinophils is increased, thereby promoting infiltration of the eosinophils into a tissue (Non-Patent Document 3), and the secretion of cytotoxic basic proteins, called an MBP (Major Basic Protein) or an ECP (Eosinophil Cationic Protein), which is present in the granules in the cell, from the granules, are caused, which consequently acts to the tissue damage (Non-Patent Document 4).
It has been reported from the studies which compare the levels of a CCR3 expression with ones in healthy people, that the mRNA levels and the protein levels are significantly increased in the airway biopsies of the patients with asthma, and that from the studies using a knockout mouse in which a CCR3 is deleted by genetic engineering technique, the studies which administer a neutralizing antibody for a CCR3 protein, or in a pathologic model, and the like due to the antigen sensitization and challenge, result in a decrease in the number of the eosinophils in a bronchoalveolar lavage fluid and an improvement of enhanced airway hyperresponsiveness (Non-Patent Documents 5 to 7).
From the findings described above, the CCR3 is deeply involved in the incidence and progression of diseases such as asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and the like, which are characterized by eosinophilic infiltration into a local lesion, and the CCR3 antagonist is expected to be effective in the prevention or treatment of these diseases in patients (Non-Patent Documents 8 to 14).
Hitherto, as the CCR3 antagonist, there have been reported a linear alkylamine derivative (Patent Document 1), a piperidine derivative (Patent Documents 2 to 4, Non-Patent Documents 11, 15 to 21), a morpholine derivative (Patent Documents 5 to 7), a pyrrolidine derivative (Patent Documents 8 and 9), a piperazine derivative (Patent Documents 10 and 11), a bicyclopiperidine derivative (Non-Patent Document 22), an azetidine derivative (Patent Document 12), and the like.
Furthermore, there has been reported a CCR3 antagonist having a tetrahydroisoquinoline skeleton (Patent Documents 13 and 14), but the compound of the present invention is different from the compounds as disclosed in these documents in the structure and the intensity of the activity.
In addition, as other tetrahydroisoquinoline compounds, there have been known a compound represented by the general formula (i) (Patent Document 15), a compound represented by the general formula (ii) (Patent Document 16), and the like, but these documents neither disclose nor suggest the CCR3 antagonistic activity, and do not disclose a specific tetrahydroisoquinoline compound represented by the formula (1) of the present invention.

(for the definition of each symbol, refer to this publication)

(for the definition of each symbol, refer to this publication)    Patent Document 1: Pamphlet of International Publication No. WO2002/59081    Patent Document 2: Pamphlet of International Publication No. WO2000/53600    Patent Document 3: Pamphlet of International Publication No. WO2005/09775    Patent Document 4: Pamphlet of International Publication No. WO2006/13073    Patent Document 5: Pamphlet of International Publication No. WO2002/26723    Patent Document 6: Pamphlet of International Publication No. WO2003/99287    Patent Document 7: Pamphlet of International Publication No. WO2006/28284    Patent Document 8: Pamphlet of International Publication No. WO2000/51607    Patent Document 9: Pamphlet of International Publication No. WO2004/58762    Patent Document 10: Pamphlet of International Publication No. WO2003/68759    Patent Document 11: Pamphlet of International Publication No. WO2006/015851    Patent Document 12: Pamphlet of International Publication No. WO2005/26113    Patent Document 13: Pamphlet of International Publication No. WO2002/26708    Patent Document 14: Pamphlet of International Publication No. WO2003/41641    Patent Document 15: Pamphlet of International Publication No. WO2002/46164    Patent Document 16: U.S. Pat. No. 5,294,621    Non-Patent Document 1: J. Biol Chem 270 (1995) 16491-16494    Non-Patent Document 2: J. Clin. Invest. 99 (1997) 178-187    Non-Patent Document 3: J. Clin. Invest. 101 (1998) 2017-2024    Non-Patent Document 4: Blood. 95 (2000) 1911-1917    Non-Patent Document 5: J. Immunol. 163 (1999) 6321-6329    Non-Patent Document 6: Proc Natl Acad Sci USA. 99 (2002) 1479-1484    Non-Patent Document 7: Am J Physiol Lung Cell Mol. Physiol. 284 (2003) L169-L178    Non-Patent Document 8: Expert Opin Investig Drugs. 9 (2000) 43-52    Non-Patent Document 9: Allergy 59 (2004) 1243-1258    Non-Patent Document 10: Curr Drug Targets Inflamm Allergy 2 (2003) 81-94    Non-Patent Document 11: Bioorganic & Medicinal Chemistry Letters 11 (2001) 1219-1223    Non-Patent Document 12: Biochem Biophys Res Commun. 339 (2006) 1217-1223    Non-Patent Document 13: J. Org. Chem. 71 (2006) 8975-8977    Non-Patent Document 14: Bioorganic & Medicinal Chemistry Letters 11 (2001) 1445-1450    Non-Patent Document 15: Chem. Pham. Bull. 51 (6) 697-701 (2003)    Non-Patent Document 16: Am J Respir Crit. Care Med Vol 165. pp 1602-1609, 2002    Non-Patent Document 17: Bioorganic & Medicinal Chemistry Letters 12 (2002) 1785-1789    Non-Patent Document 18: Bioorganic & Medicinal Chemistry Letters 14 (2004) 1645-1649    Non-Patent Document 19: J. Med. Chem. 2002, 45, 3794-3804    Non-Patent Document 20: Bioorganic & Medicinal Chemistry Letters 15 (2005) 787-791    Non-Patent Document 21: Bioorganic & Medicinal Chemistry Letters 16 (2006) 5695-5699    Non-Patent Document 22: Bioorganic & Medicinal Chemistry Letters 13 (2003) 3597-3600